We use oxygen-15 water positron emission tomography (PET) to measure regional cerebral blood flow (rCBF) as a marker of local neuronal activity in patients with schizophrenia and other neuropsychiatric disorders during performance of working memory and abstract reasoning tasks as well as during performance of matched sensorimotor control tests. In monozygotic twins discordant for schizophrenia, an area of the left inferior frontal gyrus corresponding to Brodmann's Areas 9 and 46 of the dorsolateral prefrontal cortex was lower in affected compared with unaffected twins during a frontal lobe-specific task which consistently activates this area in normal subjects. The left hippocampus and superior temporal gyrus, discriminated between affected and unaffected co-twins in each and every pair and was more active in each of the ill twins. We further localized this hyperfunctionality to the anterior (pes) portion of the hippocampal formation as opposed to more posterior hippocampal areas. The functional pattern in the amygdala, if anything, tends to be opposite, i.e. activity tends to be lower in schizophrenia. We have also shown that even when patients with schizophrenia are compared with young normal subjects with equally poor performance, they have diminished prefrontal cortical response while performing tasks with a strong working memory component. Moreover, patients with schizophrenia still show reduced activation of the prefrontal cortex when compared with healthy, elderly subjects matched with them on a one-to-one basis for WCST performance. In this schizophrenic group, reduced activation in the DLPFC correlated with more perseveration during the WCST. In contrast, in the elderly subjects DLPFC activation is preserved and does not correlate with performance, suggesting that other mechanisms may account for their cognitive impairment on this task. The prefrontal deficits in schizophrenia do not appear to be a result of chronic smoking. We are also studying other patient groups with relevance to understanding the pathophysiology of the prefrontal cortex, such as those with closed head injury. In an otherwise normal monozygotic twin who sustained a closed head injury involving the frontal lobe, the cerebral physiological response to solving a frontal lobe task was assessed both relative to his uninjured co-twin and relative to a group of 10 pairs of normal monozygotic twins. Response in the injured twin included recruitment of the hippocampus, an area not typically utilized during performance of this task. In a group of good-outcome patients with serious closed head injury and anatomically heterogeneous lesions, the brain's physiological response to performing a frontal lobe task also involves hyperactivation of the hippocampus as well as overrecruitment of some portions of the prefrontal cortex.